1. Field of the Invention
This invention relates to an oxime-based compound, more particularly to a 2-aminobenzaldehyde oxime compound that exhibits anti-inflammatory effect, a method for preparing the same, and a pharmaceutical composition containing the same.
2. Background Information
Neutrophils play a vital role in the defense of a human body against infections. In is response to inflammatory stimulus, activated neutrophils secrete a series of cytotoxins, such as superoxide anion (O2.−), precursors of other reactive oxygen species, serine proteases, and bioactive lipids.
The molecular weights of neutrophil elastase (NE, also known as leukocyte elastase or lysosomal elastase) (EC 3.4.21.37) and proteinase 3 (also known as leukocyte proteinase 3) (EC 3.4.21.76) are 29-33 kDa and 29-32 kDa, respectively. Both neutrophil elastase and proteinase 3 belong to chymotrypsin-like serine proteinase and are usually stored in azurophil granules of the neutrophils.
The activities of neutrophil elastase and proteinase 3 are modulated by endogenous inhibitor protein (such as α1-protease inhibitor and α2-macrogloblin) in the body to maintain homeostasis. The excessive proteases release may cause tissue damage, and prolonged neutrophil accumulation has an important role in the pathogenesis of inflammatory disorders.
The inflammatory disorders related to neutrophil elastase and proteinase 3 include lung injury (such as acute lung injury), chronic obstructive pulmonary disease, acute respiratory distress syndrome, emphysema, cystic fibrosis, focal cerebral ischemic, ischemic-reperfusion injury, glomerulonephritis, arthritis (such as rheumatoid arthritis), bullous pemphigoid, sepsis and Wegener's granulomatosis (see B. Korkmaz et al. (2008), Biochimie, 90:227-242; A. S. Cowburn et al. (2008), Chest, 134:606-612; Y. Nakano et al. (2009), Journal of Surgical Research, 155:311-317; M. Hayakawa et al. (2010), Shock, 33:14-18; K. J. Kwon et al. (2013), Neurosci. Lett., 548:67-72; B. Korkmaz et al. (2013), Semin. Immunopathol., 35:411-421; B. Korkmaz et al. (2013), Int. Immunopharmacol., doi: 10.1016/j.intimp.2013.07.003). Therefore, inhibition of neutrophil elastase and proteinase 3 plays an important role in the design of a drug for inflammatory disorder treatment.
Sivelestat (marketed as Elaspol) is an inhibitor for neutrophil elastase. However, the manufacturing process for sivelestat is complex and hazardous, and sivelestat has a lesser pharmacokinetic effect and is a potential toxin for organs, thereby limiting its use in clinical applications. Sivelestat is currently used for treatment of acute respiratory distress syndrome-related respiratory failure in Japan and Korea (T. Stevens et al. (2011), The Journal of Pharmacology and Experimental Therapeutics, 339:313-320).
EP 0347168 B1 discloses phenyl ester derivatives of pivalic acid having a general formula (I) as follows:

Each group of the phenyl ester derivatives of formula (I) is defined as that in the disclosure of EP 0347168 B1. From Table 1 of EP 0347168 B1, twenty compounds are proven to exhibit inhibitory effect on the activity of neutrophil elastase. The following two compounds are included in the twenty compounds:
Example 2(63): N-[O-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]glycine, wherein R1 is
R2 is H, R3 is H, m is 1, and Y is SO2; and
Example 5(3): p-[N-(O-carboxyphenyl)sulfamoyl]phenyl ester of pivalic acid, wherein R1 is
R2 is H, R3 is H, m is 1, and Y is SO2.
Han-Hsiang Wang disclosed several anthranilate derivatives, in which compounds WHH51, WHH52, and WHH53 having the following general formula (II) were proven to be capable of effectively inhibiting release of neutrophil elastase (see the thesis of “The Structure-activity Relationships Study of Anti-inflammatory Activity Anthranilate Derivatives,” Graduate Institute of Natural Products, Chang Gung University (2010)).

In compound WHH51, ring A is benzene ring, R1 is OCH3, R2 is 4-OCOC(CH3)3, W is CH, X is NH, Y is SO2, and Z is a single bond. In compound WHH52, ring A is benzene ring, R1 is OCH2CH3, R2 is 4-OCOC(CH3)3, W is CH, X is NH, Y is SO2, and Z is a single bond. In compound WHH53, ring A is benzene ring, R1 is NHCH2COOCH3, R2 is 4-OCOC(CH3)3, W is CH, X is NH, Y is SO2, and Z is a single bond.
The manufacture of the abovementioned derivatives having formulas (I) and (II) is complex and hazardous due to the use of hydrogen gas. Moreover, the effects thereof on inhibition of proteinase 3 and on treatment of inflammation disorders in vivo have not been proven. Therefore, there is a need in the art to develop novel compounds that are effective in the treatment of inflammatory disorders and that can be easily and safely manufactured.